Arginine vasopressin (AVP) and oxytocin (OT) are cyclic nonapeptides whose actions are mediated by activation of specific G protein-coupled receptors currently classifid into V1-vascular (V1R), V2-renal (V2R) and V3-pituitary (V3R) AVP receptors, as well as OT receptors (OT-R).
Oxytocin (OT) is a peptide hormone that causes the contraction of the uterus of mammals during labor. The corresponding oxytocin receptor belongs to the family of G-protein-coupled receptors and is similar to V1 and V2 vasopressin receptors. OT receptors increase dramatically during the course of pregnancy. The concentration of OT receptors has been shown to correlate with spontaneous uterine activity (M. Maggi et al. J. Clin. Endocrinol Metabol; 70; 1142, 1990). Premature labor, though, and premature birth is undesired as it represents a major cause of perinatal morbidity and mortality. Hence, the management of preterm labor represents a significant problem in the field of obstetrics.
Vasopressin is a cyclic nonapeptide hormone that exhibits a series of physiological effects including free water reabsorption, vasoconstriction, cellular proliferation and adrenocorticotrophic hormone (ACTH) secretion. In a healthy organism, vasopressin plays an important role in the homeostasis of fluid osmolality and volume status. However, in several diseases or conditions such as the syndrome of inappropriate secretion of vasopressin, congestive heart failure, arterial hypertension, liver cirrhosis, nephrotic syndrome, dysmenorrhea and ocular hypertension, vasopressin is assumed to play an important role (Thibonnier et al. Adv. Rev. Pharmacol. Toxicol., 2001; 41: 175-202; Thibonnier et al. Adv. Exp. Med. Biolog.; 1998; 449: 251-203).
In recent years, strong evidence has accumulated indicating that the hormone oxytocin plays a major role in iniating labor in mammals, in particular in humans. Thereby, it is assumed that oxytocin exerts said effect in a direct as well as an indirect way, by contracting the uterine myometrium and by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. These prostaglandins may furthermore play a role in the cervical ripening process. This “up-regulation” of oxytocin receptors and increased uterine sensitivity seems to be due to trophic effects of rising plasma levels of estrogen towards term. By down-regulating oxytocin, it is expected that both the direct (contractile) and indirect (increased prostaglandin synthesis) effects of oxytocin on the uterine could be blocked. An oxytocin modulator, e.g. blocker or antagonists would likely be more efficacious for treating preterm labor than current regimens. Moreover, as oxytocin at term has only an effect on the uterus, such an oxytocin modulator would have only few or no side effects.
A further condition being related to oxytocin is dysmenorrhea, which is characterised by cyclic pain associated with menses during ovulatory cycles. Said pain is believed to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium. By blocking both the indirect and direct effects of oxytocin on the uterus, an oxytocin antagonist is belived more efficacious for treating dysmenorrhea than current regimens.
Some agents counteracting the action of oxytocin are currently used in clinical studies. Such tocolytic agents (i.e. uterine-relaxing agents) include beta-2-adrenergic agonists, magnesium sulfate and ethanol. The leading beta-2-adrenergic agonists is Ritodrine, which causes a number of cardiovascular and metabolic side effects, including tachycardia, increased renin secretion, hyperglycemia and reactive hypoglycemia in the infant. Further beta-2-adrenergic agonists, including terbutaline and albuterol have side effects similar to those of ritodrine. Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired. Ethanol is as effective as ritodrine in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress that administration of ritodrine does.
The principal drawback to the use of peptide antagonists including also atosiban is the problem of low oral bioavailability resulting from intestinal degradation. Hence, they must be administered parenterally.
The development of non-peptide ligands for peptide hormone receptors are expected to overcome this problem. Small molecule selective oxytocin antagonists have been reported by Merck. In addition to cyclic hexapeptides, Merck suggested indanylpiperidines and tolyl-piperazines as orally deliverable OT antagonists (Evans et al. J. Med. Chem., 35, 3919 (1992). In WO 96/22775 and U.S. Pat. No. 5,756,497 Merck reported benzoxazinylpiperidines or benzoxazinones as OT receptor antagonists.
Specific sulfonamides have been reported to antagonize ocytocin at the ocytocin receptor. Elf Sanofi's EP-A-0469984 and EP-A-0526348 report N-sulfonyl indolines acting as antagonists of the vasopressin and the oxytocin receptors.
It is an object of the present invention to provide substances which down-regulate—up to antagonizing—the function of OT and/or V1a in disease states in animals, preferably mammals, especially in humans. It is another object of this invention to provide a method of antagonizing the functions of the OT and/or V1a receptors in disease states of mammals. It is also an objective of the present invention to provide small molecule chemical compounds for the modulation, preferably the down-regulation or even antagonisation of the oxytocin receptor. Moreover, it is an objective of the present invention to provide methods for preparing said small molecule chemical compounds. It is furthermore an object of the present invention to provide a new category of pharmaceutical formulations for the treatment of preterm labor and dysmenorrhea, and/or diseases mediated by the oxytocin receptor. It is finally an object of the present invention to provide a method of treating or prevent disorders mediated by the oxytocin receptor, like preterm labor, inappropriate secretion of vasopressin, congestive heart failure, arterial hypertension, liver cirrhosis, nephrotic syndrome, dysmenorrhea and ocular hypertension with oxytocin and/or vasopressin antagonists, acting for example by antagonising the binding of oxytocin and/or vasopressin to their receptor.